Method and system for real-time vibroacoustic condition monitoring and fault diagnostics in solid dosage compaction presses

ABSTRACT

The present invention relates to methods and systems for condition monitoring of and/or fault diagnostics in solid dosage compaction presses and, more particularly, to methods and systems for real-time vibroacoustic condition monitoring of and/or fault diagnostics in solid dosage compaction presses.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Non-Provisional patentapplication Ser. No. 14/149,356 filed on Jan. 7, 2014, which claimspriority to U.S. Non-Provisional patent application Ser. No. 11/725,963filed on Mar. 20, 2007, which claims priority to Provisional PatentApplication Ser. No. 60/783,574 filed on Mar. 20, 2006 entitled Methodfor Monitoring and Characterization of Solid Dosage during Compactionand Provisional Patent Application Ser. No. 60/808,537 filed on May 26,2006 entitled Method for Non-contact Mechanical PropertyCharacterization and Monitoring of Drug Tablets, which are incorporatedherein by reference in their respective entireties.

FIELD OF INVENTION

The present invention relates to methods and systems for conditionmonitoring of and/or fault diagnostics in solid dosage compactionpresses and, more particularly, to methods and systems for real-timevibroacoustic condition monitoring of and/or fault diagnostics in soliddosage compaction presses.

BACKGROUND OF INVENTION

In order to promote comprehensive quality assurance monitoring in thepharmaceutical industry the Food and Drug Administration (FDA) hasinitiated a program entitled the Process Analytical Technology (PAT)which is often defined as “a system for designing, analyzing, andcontrolling manufacturing through timely measurements (i.e. duringprocessing) of critical quality and performance attributes of raw andin-process materials, and processes with the goal of ensuring finalpharmaceutical product quality.” It is important to note that the termanalytical in PAT is viewed broadly to include chemical, physical,microbiological, mathematical, and risk analysis conducted in anintegrated manner. The approaches detailed in this disclosure aretargeted for such monitoring and evaluation tasks.

Physical properties and mechanical integrity of drug tablets oftenaffect their therapeutic functions. This disclosure presentsnon-contact/non-destructive techniques for determining the mechanicalproperties of coated tablets, such as Young's moduli, Poisson's ratiosand mass densities as well as the thickness of the coating layer usingan air-coupled approach is presented. Due to the elevated regulatory andcompetitive requirements, the demand for measuring and evaluating themechanical properties of drug tablets has been increasing in thepharmaceuticals industry.

Compaction is a common production method for solid dosage formation frompowder and/or granular materials in various industries. Solid dosage(e.g. drug tablets) cores are manufactured by applying pressure to apowder bed to compress the powder into a (porous) coherent/solid form.Compaction represents one of the most important unit operations in thepharmaceuticals industry. Physical and mechanical/elastic properties ofthe tablets, such as density, hardness and/or mechanical strength aswell as geometric features, are determined during the compactionprocess. These properties can play crucial roles in pharmaceuticaleffectiveness and functions of a tablet such as tablet integrity anddrug availability. The uniaxial compaction of a pharmaceutical powderresults in an anisotropic and heterogeneous tablet with variations insuch properties as density, porosity and mechanical strength throughoutthe tablet. During the compaction, various types of defect types can becreated in tablets during compaction process, such as capping, chipping,cracking, and splitting. While many of these defect types can be easilyidentifiable through visual inspections of their exteriors, the defectsformed in the interior of a tablet such as cracks are considerably moredifficult to detect. Such invisible defects can result in functionallycompromised tablets.

Some of the commonly defects occurred during compaction operation are asfollows.

Capping is the term used, when the upper or lower segment of the tabletseparates horizontally, either partially or completely from the mainbody of a tablet and comes off as a cap, during ejection from the tabletpress, or during subsequent handling. Lamination is the separation of atablet into two or more distinct horizontal layers. The main reason forthese types of defect is that the air-entrapment in a compact duringcompression, and subsequent expansion of tablet on ejection of a tabletfrom a die causes capping and lamination.

Chipping is defined as the breaking of tablet edges, while the tabletleaves the press or during subsequent handling and coating operations.The major reasons of chipping include incorrect machine settings andspecially mis-set ejection take-off.

Cracking (small, fine cracks) observed on the upper and lower centralsurface of tablets, or very rarely on the sidewall is often as a resultof rapid expansion of tablets, especially when deep concave punches areused. Many mechanical and materials factors such as stress localizationand poor adhesion conditions can cause cracks in a tablet core.

Cracking/Splitting is defect in which the film either cracks across thecrown of the tablet (cracking) or splits around the edges of the tablet(Splitting) under internal stresses in the film that exceeds tensilestrength of the film. Sticking refers to the tablet material adhering tothe die wall. Filming is a slow form of sticking and is largely due toexcess moisture in the granulation (due to improperly dried orimproperly lubricated granules).

Picking is the term used when a small amount of material from a tabletis sticking to and being removed off from the tablet-surface by a punchface. Picking defect is more prevalent on the upper punch faces than onthe lower ones. If tablets are repeatedly manufactured in this stationof tooling, the size of the defect becomes larger the more and morematerial getting added to the already stuck material on the punch face.Picking is of particular concern when punch tips have engraving orembossing letters, as well as the granular material is improperly dried.

When the tablets adhere, seize or tear in the die, a film is formed inthe die and ejection of tablet is hindered. This type of defect istermed as binding. With excessive binding, the tablet sides are crackedand it may crumble apart. Binding is usually due to excessive amount ofmoisture in granules, lack of lubrication and/or use of worn dies.

In recent years, deformation and compaction characteristics of thetableting materials have been intensely studied. See: Fell J. T.,Newton, J. M., 1968, Tensile strength of lactose tablets, The Journal ofPharmacy and Pharmacology, 20, 657-659; Fell J. T., Newton, J. M., 1970,The prediction of the tensile strength of tablets, The Journal ofPharmacy and Pharmacology, 22, 247; Hancock, B. C., Colvin, J. T.,Mullarney, M. P. Zinchuk, A. V., 2003, The relative densities ofpharmaceutical powders, blends, dry granulations, and immediate-releasetablets, Pharmaceutical Technology, 27, 64-80 (Payne et al.); R. S.,Roberts R. J., Rowe R. C., McPartlin M., Bashall A., 1996, Themechanical properties of two forms of primidone predicted from theircrystal structures, International Journal of Pharmaceutics, 145, 165-173(Robert et al.); Roberts R. J., Payne R. S., Rowe R. C., 2000,Mechanical property predictions for polymorphs of sulphathiazole andcarbamazepine, European Journal of Pharmaceutical Sciences, 9, 277-283;Roberts R. J., Rowe R. C., 1987, The Young's modulus of pharmaceuticalmaterials, International Journal of Pharmaceutics, 37, 15-18; Bassam F.,York P., Rowe R. C., Roberts R. J., 1990, Young's modulus of powdersused as pharmaceutical excipients, International Journal ofPharmaceutics, 64, 55-60; and Rigdway K., Aulton M. E., 1970, Thesurface hardness of tablets, Journal of Pharmacy and Pharmacology, 22,70-78, all hereby incorporated herein by reference.

One main objective has been to determine the powder behavior duringcompaction and to understand the effect of the processing of tabletingstages on the compaction properties of final products. Even thoughphysical-mechanical properties of tablets are known to influence thetablet chemical and physical stability, accuracy of dosage andappropriate self life, few studies have focused on properties such asthe Young's modulus, tensile strength and Poisson's ratio of the coreand coating layer of the tablets. See Felton L. A., Shah N. H., ZhangG., Infeld M. H., Malick A. W., McGinity J. W., 1996,Physical-mechanical properties of film-coated soft gelatin capsules,International Journal of Pharmaceutics, 127, 203-211 (Felton et al.);and Stanley P., Rowe R. C. and Newton J. M., 1981, Theoreticalconsiderations of the influence of polymer film coatings on themechanical strength of tablets. Journal of Pharmacy and Pharmacology,33, 557-560 both hereby incorporated by reference.

Fell and Newton as cited above investigated the tensile strength of thetablets by diametrical compression tests. Felton et al. as cited abovestudied the physical-mechanical properties of film-coated tabletsincluding tensile strength, Young's modulus and tensile roughness usinga diametrical compression test. In a diametrical compression test asdiscussed by Fell and Newton, the tablet is placed between two jaws andcrushed. The force applied to break the tablet is recorded along withthe outer dimensions of the tablet and tensile strength is calculated.The determination of the tensile strength of individual tabletcomponents is used to predict the resultant tensile strength of tabletas a whole.

An important objective of the physical-mechanical property of coatingfilms is to predict the stability and release property of film-coateddosage forms. Tablet coating has been effectively used to protect thedosage form from its environment, to control the release of activeingredients in the body, and to prevent interactions betweeningredients. Additionally, tablet coating has improved the mechanicalstrength of the dosage form to preserve tablet integrity duringpackaging and shipping. Several researchers have focused on tensilestrength and the elastic modulus of free-standing films prepared viaaqueous coating technology. See Gutierrez-Rocca J. C. and McGinity J.W., 1993, Influence of aging on the physical-mechanical properties ofacrylic resin films cast from aqueous dispersions and organic solutions,Drug Development and Industrial Pharmacy, 19, 315-332; Gutierrez-RoccaJ. C. and McGinity J. W., 1994, Influence of water soluble and insolubleplasticizers on the physical and mechanical properties of acrylic resincopolymers, International Journal of Pharmaceutics, 103, 293-301; andObara S. and McGinity J. W., 1994; Properties of free films preparedfrom aqueous polymers by a spraying technique; Pharmaceutical Research,11, 1562-1567, all hereby incorporated by reference. The Obara andMcGinty study cited above compared the properties of cast films tosprayed films. It has been reported that the mechanical propertyvariation of the sprayed films are lower and their tensile strength arehigher than those of the cast films.

Payne et al. and Roberts et al. (both cited above) developed a molecularmodeling approach for predicting Young's moduli of compacts andtableting materials. A mechanical model of crystal structure was used todetermine the crystal lattice energy, from which Young's moduli of aseries of compacts prepared from aspirin and polymorphs of primidone,carbamazepine and sulphathiazole could be extracted. However, reportedlyit is difficult to obtain the bulk elastic properties of tabletmaterials from the first principles based on molecular dynamicsimulations.

Acoustic emission (AE) techniques during processes have been widelyutilized in the pharmaceuticals industry due to its cost effective andnoninvasive nature for monitoring granular materials to predict theirflow, particle size and compaction properties of the final granules.Wong et al. differentiate the deformation mechanisms of single crystalsof lactose monohydrate and anhydrous lactose by acoustic emission. It isreported that acoustic emission techniques can be employed to predictthe compaction properties and brittleness of tableting materials if thebulk material is characterized by a single-crystal. See: Wong D. Y. T.,Waring M. J., Wright P. and Aulton M. E., 1991, Elucidation of thecompressive deformation behavior of a-lactose monohydrate and anhydrousa-lactose single crystals by mechanical strength and acoustic emissionanalyses, International Journal of Pharmaceutics, 72, 233-241 (Wong etal.) hereby incorporated by reference.

Waring et al. and Hakanen and Laine investigated the acoustic emissionof lactose, sodium chloride, microcrystalline cellulose and paracetamolduring compression using an acoustic transducer coupled to a portableactivity meter. See Hakanen A., Laine E., 1993, Acoustic emission duringpowder compaction and its frequency spectral analysis, Drug Developmentand Industrial Pharmacy, 19, 2539-2560 (Waring et al.); and Hakanen A.,Laine E., 1995, Acoustic Characterization of a micro-crystallinecellulose powder during and after its compression, Drug Development andIndustrial Pharmacy, 21, 1573-1582, hereby incorporated by reference. Bycomputationally analyzing the acoustic peaks related with the particlecompression and decompression, it is concluded that the deformationmechanism and capping tendency can be predicted (See Hakanen and Lainecited above). Measuring acoustic emission from process chambers is alsoused for the identification of various phenomena that can occur duringpowder compaction of pharmaceutical products, such as granularrearrangement, fragmentation, visco-plastic deformation of grains orgranules. See Serris E., Camby-Perier L., Thomas G., Desfontaines M.,Fantozzi G., 2002. Acoustic Emission of Pharmaceutical Powders duringCompaction, Powder Technology, 128, 2-3, 296-299. Acoustic emission is apassive acoustic technique thereby control over the nature of excitationis often limited.

Hardy and Cook reviewed the use of near infrared spectroscopy (NIR), anon-destructive remote technique as being primarily used for monitoringand predicting the end-points of granulation and drying operations. SeeHardy I. J. and Cook W. G., 2003, Predictive and correlative techniquesfor the design, optimization and manufacture of solid dosage forms,Journal of Pharmacy and Pharmacology, 55 (1), 3-18 hereby incorporatedby reference. The potential use of NIR has also been studied to predicttablet hardness. See Morisseau K. M., Rhodes C. T., 1997, Near-infraredspectroscopy as a nondestructive alternative to conventional tablethardness testing, Pharmaceutical Research, 14 (1), 108-111; Kirsch J.D., Drennen J. K., 1999, Nondestructive tablet hardness testing bynear-infrared spectroscopy: a new and robust spectral best-fitalgorithm. Journal of Pharmaceutical and Biomedical Analysis, 19 (3-4),351-362; Chen Y. X., Thosar S. S., Forbes s R. A., Kemper M. S.,Rubinovitz R. L., Shukla A. J., 2001, Prediction of drug content andhardness of intact tablets using artificial neural network andnear-infrared spectroscopy, Drug Development and Industrial Pharmacy, 27(7), 623-631;

Donoso M., Kildsig D. O., Ghaly E. S., 2003, Prediction of tablethardness and porosity using near-infrared diffuse reflectancespectroscopy as a nondestructive method, Pharmaceutical Development andTechnology, 8 (4), 357-366; Blanco M., Alcala M., 2006, Contentuniformity and tablet hardness testing of intact pharmaceutical tabletsby near infrared spectroscopy—A contribution to process analyticaltechnologies, Analytica Chimica Acta, 557 (1-2): 353-359; and Otsuka M.,Yamane I., 2006, Prediction of tablet hardness based on near infraredspectra of raw mixed powders by chemometrics, Journal of PharmaceuticalSciences, 95, 1425-1433; all hereby incorporated by reference. However,its sensitive calibration and validation requirements for tablethardness models remain a challenge since it is known that a slightvariation in spectral peaks could invalidate a model.

Many solid pharmaceutical dosage mediums are produced with coatings,ideally the tablet should release the material gradually and the drugshould be available for digestion beyond the stomach. Tablet coats servea wide range of purposes, such as to control release of activeingredients in the body, to avoid irritation of esophagus and stomach,and to protect the stomach from high concentrations of activeingredients, to improve drug effectiveness and stability and to regulateand/or extend dosing interval. In addition coats extend shelf life byprotecting the ingredients from degradation, and to enhance the drugstability; that is to protect the drug from moisture, environmentalgases, temperature variations and light, to provide a barrier tounpleasant taste or odor, and to improve appearance and acceptability aswell as product identity (Cetinkaya et al., 2006; Mathiowitz, 1999).Coatings that form a controlling barrier to the release of the activeingredient and impart a sustained release of the drug are valuabledelivery systems that provide convenience as well as patient compliance.Especially this is true for functional coatings such as an entericcoating which is designed to protect the tablet from the acidicenvironment of the stomach, resulting in drug release in the higher pHenvironment of the small intestine. Non-uniformity and/or surface orsub-surface defects of the tablet coating can compromise the desireddose delivery and bioavailability of the drug tablet as well as someother functions. Therefore, evaluating the properties of pharmaceuticalcoatings such as thickness and uniformity is important for demonstratingadequate process controls and quality and for ensuring optimalperformance of the final product. As discussed above, in relation toquality and assurance, the Food and Drug Administration (FDA) hasinitiated a program entitled the Process Analytical Technology (PAT) toaddress various aspects of manufacturing problems in the pharmaceuticalsindustry. The PAT initiative is intended to improve consistency andpredictability of drug action by improving quality and uniformity ofpharmaceutical materials (Hussain et al., 2004).

In the pharmaceuticals industry, various techniques have been employedin coating thickness measurements such as ultrasonic measurements(Akseli et al., 2007), laser induced breakdown spectroscopy (LIBS)(Mowery et al., 2002), x-ray fluorescence method (Behncke, 1984), shortpulsed of electromagnetic radiation (e.g. TeraHertz pulsed spectroscopy)(Fitzgerald et al., 2005), scanning thermal microscopy and Fouriertransform infrared (FTIR) spectroscopy (Felton, 2003). In contactpulse-echo acoustic measurements, short ultrasonic pulses are generatedby a piezoelectric transducer to transmit through the tablet. Theultrasonic pulse is reflected from the back side of the tablet andreturned to the measurement surface via the shortest possible path. Thereflected waveforms are captured by the same transducer and digitized inthe oscilloscope. Measuring the displacement of the first back-wall echofrom the start of the transmission peak, the longitudinal velocity ofsound can be computed (Akseli et al., 2007). The thickness can then becalculated from the calibration of the time base. Throughout thesemeasurements, coupling medium (water, grease, oil, and couplant gel) isrequired for facilitating the transmission of ultrasonic energy from thetransducer into the test specimen.

Short pulsed of electromagnetic radiation and its reflections frominterfaces (e.g. TeraHertz pulsed spectroscopy) is used for the analysisof coating thickness of tablets however due to its high cost it isdifficult to use this technique in practice. Scanning thermalmicroscopy, laser induced breakdown spectroscopy (LIBS), x-rayfluorescence method and Fourier transform infrared (FTIR) spectroscopyare either expensive or unavailable for rapid online measurements forcoating thicknesses of drug tablets. The proposed technique haspotential to fulfill a major need in the analysis of drug deliverymechanisms.

Other relevant non-contact techniques for mechanical propertydetermination adopted in various industrial applications include: (i)EMAT (Electro-Magnetic Acoustic Transducer)-based systems, (ii) opticalmethods, (iii) spectroscopy-based approaches (IR, near-IR, Ramanscattering, Plasmon resonance). Nondestructive testing technologiesbased on EMATs are inapplicable to the determination of mechanicalproperties of tablets since tablet materials are typically notelectrically conductive. Optical methods are often limited to surface,or near-surface properties, and are often irrelevant in sub-surfacemechanical property analysis since, in general, drug tablets and coatinglayers are opaque in the visible and non-visible ranges. In tabletintegrity applications, optical techniques are considered indirectmethods for mechanical property monitoring and evaluation. For severalyears, spectroscopic techniques have been used in monitoring variousprocess parameters such as moisture (water and/or alcohol levels) andblending properties of powders. In these measurements, surfaceproperties are sufficient but the penetration of the electromagneticwaves inside the tablet is typically not required and/or not possible.There is no general method to predict the Young's modulus and Poisson'sratios of the core and coating layer of a tablet from the properties ofits constituent components even if exact process steps are known.Non-contact acoustic techniques, detailed in this disclosure, havecertain advantages in testing and evaluating the mechanical integrity ofthe core and the coating layer of drug tablets because of the abilityfor acoustic waves to penetrate the tablet surface and to vibrate entiretablet structures.

Background of Invention Section Disclaimer: To the extent that specificpatents/publications/products are discussed above in this Background ofInvention Section or elsewhere in this application, these discussionsshould not be taken as an admission that the discussedpatents/publications/products are prior art for patent law purposes. Forexample, some or all of the discussed patents/publications/products maynot be sufficiently early in time, may not reflect subject matterdeveloped early enough in time and/or may not be sufficiently enablingso as to amount to prior art for patent law purposes. To the extent thatspecific patents/publications/products are discussed above in thisBackground of Invention Section and/or throughout the application, thedescriptions/disclosures of which are all hereby incorporated byreference into this document in their respective entirety(ies).

SUMMARY OF INVENTION

A first method of detecting, monitoring or characterizing a drug tabletduring compaction includes: forming a tablet from a powder core in acompactor; transmitting acoustic waves into the powder core while thetablet is being formed; receiving acoustic waves from the powder corewhile the tablet is being formed; measuring data received from thereceived acoustic waves; calculating the data; and presenting the data.The acoustic waves are generated and received by transducers embedded indie and punches of the compactor. The instrumentation and signalprocessing are used for the measuring, calculating and presenting thedata. The instrumentation includes a pulser/receiver unit, a digitizingoscilloscope, a computer and a computer program product. The computerprogram product is a computer usable medium having computer readableprogram code means embodied in the medium for detecting, monitoring orcharacterizing a drug tablet during compaction. The detecting,monitoring or characterizing includes transmitting acoustic waves intothe powder core while the tablet is being formed; receiving acousticwaves from the powder core while the tablet is being formed; measuringdata received from the received acoustic waves; calculating the data;and presenting the data.

The apparatus for detecting, monitoring or characterizing a drug tabletduring compaction includes a compactor having a plurality of punches anddie; a means for forming a tablet from a powder core; a plurality oftransducers for transmitting acoustic waves into the powder core whilethe tablet is being formed; a plurality of transducers for receivingacoustic waves from the powder core while the tablet is being formed;instrumentation coupled to the transducers measuring, calculating andpresenting the data. The transducers for transmitting acoustic signalwaves to the powder core and the transducers for receiving acousticwaves from the powder core may be single transducer performing bothfunctions.

Subsequent production decisions (e.g. rejection or continuation of thetablet in the manufacturing process) on the tablet can be made based onthe processing of the acoustic signals. The main advantage of theinvention is that it provides early warning on the mechanical andgeometric state of a tablet during compaction to the operator before anumber of other processing operations are applied.

A second method determines the mechanical characteristics and coatingthickness of a tablet by exciting the tablet with an acoustic field.This followed with acquiring reflected signals from the tablet anddigitizing the reflected signals. The mechanical characteristics areextracted from the digitized signals having resonance frequencies withina certain bandwidth. The exciting of the tablet includes vibrating thetablet. The acquiring of reflected signals includes detecting a shift ofa reflected laser beam with an interferometer. The digitizing of thereflected signal is performed by an oscilloscope or by a sampling board.The extracting of the mechanical characteristics from the digitizedsignals having resonance frequencies within a certain bandwidth isachieved using an iterative process. The iterative process is performedby a computer using a computer program product. The mechanicalcharacteristics being measured include Young's modulus, Poisson'sratios, material mass densities and tablet coating thickness.

The computer program product is a computer usable medium having computerreadable program code means embodied in the medium for determining themechanical characteristics and coating thickness. Determining themechanical characteristics and coating thickness includes exciting thetablet with an acoustic field; acquiring reflected signals from thetablet; digitizing the reflected signals; and extracting mechanicalcharacteristics and coating thickness from the resonance frequencieswithin a certain bandwidth using an iterative process.

The apparatus for non-contact mechanical property characterization ofdrug tablets includes: a vacuum wand; an air coupled transducer; aninferometer; a vacuum control unit; pulse generating device; andmeasurement and calculation instrumentation. The vacuum control unit andvacuum wand retrieves and supports the tablets to be characterized. Theair coupled transducer excites the tablets with acoustical waves. Theinferometer measures a vibrational response from the excited tablets ina non-contact manner. The instrumentation digitizes and performs aniterative calculation of the vibrational responses to determine themechanical characteristics of the tablet. The instrumentation furthercomprises a computer and a computer program product.

Embodiments of the present invention can also include a method andsystem for in-die and out-of-die monitoring and/or characterizingmulti-component tablets (i.e., dry-coated tablets, tablet-in-tabletsolid dosage, bilayer tablets, tri-layer tablets, osmotic tablets, andso on, as should be understood by those of skill in the art) based onacoustic and vibrational spectroscopy, which are disclosed. Alone with anumber of production tools, a compaction press is often employed to makesuch products by pharmaceutical, nutraceutical, cosmetics, metal andceramic parts, powder and various other manufacturers for compactingpowder/granular material into a solid form, as discussed herein. Thedry-coated tablet dosage form (i.e., the tablet-in-tablet design) is aspecial form of multi-component tablets. Multi-component tablet formtypically is a time- and rate-controlled drug delivery device, whichconsists of a core tablet and an outer layer that is considerablythicker than typical tablet coats, and which completely surrounds thecore (inner) tablet. Multi-component tablets format (tablet-in-tabletsolid dosage) is adopted in various industries and applications fromdetergent to pharmaceutical manufacturing. Due to various components andinterfaces, such products are more complex and, thus, prone to defectsand failure, thus their characterization and testing is of practicalinterest for product quality improvements and regulatory requirements.

The disclosed approach as set forth in these additional embodiments isfor determining the mechanical (physical), interfacial bonding andgeometric (size, wall/core thicknesses, core eccentricity, and so on)quality of such multi-component products by acquiring and processingmulti-component products' responses to acoustic and vibrationalexcitations. These mechanical (physical), interfacial, and geometricproperties affect the modal structure of the tablet. In the disclosedapproach, the variations in the modal response (resonance frequenciesand mode shapes) are related to the mechanical (physical), interfacial,and geometric properties using analytical/computational and statisticalmethods, as disclosed herein. The disclosed method and system can beadopted for inline/online monitoring and characterization of such tabletproducts as well as post-production quality monitoring andcharacterization applications when the product is still in theproduction and/or in the post-production phase.

Embodiments of the present invention can also include a method andsystem for detecting and monitoring stiction and tooling materialmodifications on punch and die surfaces during compaction based onacoustic/ultrasonic waves. These embodiments are more fully described inthe Detailed Description section below. The material stiction occursduring compaction due to decreased lubricants at the interfaces and/orincreased adhesion of powders and other materials used in compaction.Geometric and material modification (e.g. pitting, plastic deformations,etc.) on the punch and die surfaces and bodies occurs because of variousreasons such as material fatigue, micro-structure defects, crackformation, cyclic thermal loading, dynamic loading, chemicalinteractions so on. The disclosed approach is based on the detection ofthe interactions of acoustic/ultrasonic waves with excess materials onthe surfaces of punches and dies and/or geometric/property modificationsin the materials of these surfaces. Such detections are used todetermine the material addition (due to stiction) to the surfaces ofinterest and the surface and body modifications in the punch/diematerials.

Embodiments of the present invention can also include a method andsystem for real-time vibroacoustic condition monitoring of and/or faultdiagnostics in solid dosage compaction presses. These embodiments aremore fully described in the Detailed Description section below. Acompaction press is an essential piece of machinery for pharmaceutical,nutraceutical, cosmetics, metal and ceramic parts, powder and variousother manufacturers for compacting powder/granular material into a solidform. During its operation, a compaction press generates vibrational andacoustic signals due to a vast array of interactions between itscomponents and parts, such as punches and dies, rollers, bearings, driveshafts, and motors. In accordance with an embodiment of the presentinvention, the condition (working, non-working, working according to acertain specification etc.) and wear states of the components and partsof a compaction press can be monitored by acquiring such vibrational andacoustic signals using accelerometers and wide-spectrum acousticsensors, wirelessly transmitting them to a remote control station(preferably in real-time), and signal-processing the signals todetermine condition and fault level/state of various parts andcomponents of the compaction press. The process data can be used forpreventive maintenance and remote process monitoring.

BRIEF DESCRIPTION OF DRAWINGS

The foregoing aspects and many of the attendant advantages of thisdisclosure will become more readily appreciated as the same becomebetter understood by reference to the following detailed description,when taken in conjunction with the accompanying drawings, wherein:

FIG. 1 illustrates four transducers embedded in the upper and lowerpunches of a compaction device and the die generate and detect acousticwaves through the power core during compaction;

FIG. 2 illustrates examples of typical punches and die sets;

FIG. 3A illustrates schematics of a sample tablet mounting apparatuswith the vacuum wand configuration;

FIG. 3B illustrates the instrumentation diagram of the experimentalsetup;

FIG. 4A illustrates an image of the bottom excitation configurationusing a 120 kHz transducer with a vacuum wand holding the tablet inplace;

FIG. 4B illustrates an image of the bottom excitation configurationusing a 120 kHz transducer with a vacuum wand holding the tablet inplace;

FIG. 5A illustrates the dimensions of a coated tablet with its top view;

FIG. 5B illustrates the dimensions of a coated tablet with its frontview;

FIG. 5C illustrates the dimensions of a coated tablet with its sideview;

FIG. 5D illustrates the dimensions of a coated tablet with itsperspective view;

FIG. 6A illustrates waveforms indicating the time-of-flight and multiplereflections across the tablet cross-section for a first tablet in thepulse-echo mode;

FIG. 6B illustrates waveforms indicating the time-of-flight and multiplereflections across the tablet cross-section for a second tablet(different from the first tablet shown in FIG. 6A) in the pulse-echomode;

FIG. 7A illustrates the transient displacement of a spot on the activesurface of the transducer under a square pulse excitation;

FIG. 7B illustrates the frequency response of a spot on the activesurface of the transducer under a square pulse excitation;

FIG. 8A illustrates the waveforms of a first tablet held with the vacuumwand;

FIG. 8B illustrates the waveforms of a second tablet held with thevacuum wand;

FIG. 8C illustrates a comparison of the first tablet's (of FIG. 8A) andthe second tablet's (of FIG. 8B) frequency responses;

FIG. 9 illustrates the normalized sensitivities of the resonancefrequencies of Tablet 1 to the changes in Ecore, ρcore, νcore, Ecoat,ρcoat, and νcoat for the modes 8, 9, 11, 13, 14 and 15;

FIG. 10A illustrates the convergence of Ecore of the Tablet 1 during thesensitivity iterations;

FIG. 10B illustrates the convergence of ρcore of the Tablet 1 during thesensitivity iterations;

FIG. 10C illustrates the convergence of νcore of the Tablet 1 during thesensitivity iterations;

FIG. 10D illustrates the convergence of Ecoat of the Tablet 1 during thesensitivity iterations;

FIG. 10E illustrates the convergence of ρcoat of the Tablet 1 during thesensitivity iterations;

FIG. 10F illustrates the convergence of νcoat of the Tablet 1 during thesensitivity iterations;

FIG. 11 illustrates a flow chart for the iterative process;

FIG. 12A illustrates examples of potential uses of the tablet monitoringevaluation platform;

FIG. 12B illustrates examples of potential uses of the tablet monitoringevaluation platform including a desktop testing unit and an onlinemonitoring system;

FIG. 13 illustrates a connectivity diagram of various components of amonitoring system;

FIG. 14 is a picture of a vertical cross section of a sample dry coatedtablet showing its structural components (core and coat layers) andinterfaces;

FIG. 15A is a picture showing a typical tri-layered tablet design, whichis another type of a multi-component tablet (as compared to FIG. 14);

FIG. 15B is a picture showing a commercial tablet with complex layeredtablet-in-table design, which is another type of a multi-componenttablet (as compared to FIG. 14);

FIG. 15C illustrates a compound tablet design with osmotic pumps andtheir delivery ports (orifices), which is another type of amulti-component tablet (as compared to FIG. 14);

FIG. 15D illustrates another type of a multi-component tablet (ascompared to FIG. 14);

a-d are pictures showing various other types of multi-component tablets(as compared to FIG. 14) from consumer markets and the pharmaceuticalindustry;

FIG. 16 is a schematic representation of a vibroacoustic excitation anddetection system, which is used for in-die monitoring and/orcharacterizing multi-component tablets in accordance with an embodimentof the present invention;

FIG. 17 is a schematic representation of a vibroacoustic excitation anddetection system, which is used for out-of-die monitoring and/orcharacterizing multi-component tablets in accordance with an embodimentof the present invention;

FIG. 18 is a schematic representation of a system for detecting andmonitoring stiction and tooling material modifications on the surfacesand bodies of punches and dies, in accordance with an embodiment of thepresent invention; and

FIG. 19 is a photograph of an experimental set-up of a system fordetecting and monitoring stiction and tooling material modifications onthe surfaces and bodies of punches and dies with an instrumented upperpunch and tooling housing apparatus, in accordance with an embodiment ofthe present invention.

FIG. 20 is a graph showing tip-only waveforms from a wired (solid lines)and wireless (dotted lines) set-ups, demonstrating the differencebetween directly wired data and the noisy wireless data, in accordancewith an embodiment of the present invention.

FIG. 21 is a photograph of a compactions with material deposition(modifications) in the inner walls of a die, in accordance with anembodiment of the present invention.

FIG. 22 is a schematic representation of a system 2200 for vibroacousticcondition monitoring of and/or fault diagnostics in solid dosagecompaction presses, in accordance with an embodiment of the presentinvention.

DETAILED DESCRIPTION

This application discloses methods of and devices for non-contactmechanical property determination and coat thicknesses of drug tablets.

A first method described in this disclosure is to detect, monitor andcharacterize a drug tablet during compaction by means of transmittingand receiving acoustic waves into the powder core, as it is formed in apress (compactor), via transducers embedded in the compactor die andpunches. Subsequent production decisions (e.g. rejection or continuationof the tablet in the manufacturing process) on the tablet can be madebased on the processing of the acoustic signals. The main advantage ofthis method is that it provides an early warning on the mechanical andgeometric state of a tablet during compaction to the operator before anumber of other processing operations are applied.

The objective of this method is to characterize and to monitor themechanical (physical) and geometric state of the powder core in the dieduring compaction in a real-time manner. The characterization anddetection/monitoring system consists of a plurality of transducers thatgenerate and receive high frequency acoustic wave fields as well aselectronic instrumentation and signal processing software.

This method detects, monitors and characterizes a drug tablet duringcompaction by means of transmitting and receiving acoustic waves intothe powder core, as it is formed in a press (compactor), via transducersembedded in the compactor die and punches as illustrated in FIG. 1. Animage of a typical punches and die set is illustrated in FIG. 2.

FIG. 1 illustrates a compactions device 10 with four transducersembedded 12, 14, 16, and 18 embedded within an upper punch 20, a lowerpunch 22, a first die 24 and a second die 26. These transducers emitacoustic waves towards the punched tablet and measure its mechanicalcharacteristic. These measurements are coupled to instrumentationcalculate and present the results of these measurements. The propagationproperties of the powder core in the die during compaction depend on themechanical properties and their distributions as well as geometricfactors (such as delamination zones and cracks). Therefore, byextracting these properties from the transmitted acoustic wave throughthe powder core, useful information about the material and geometricproperties of the powder core can be obtained via instrumentation andsignal processing.

Typical instrumentation in such a monitoring and characterization systemconsists of a pulser/receiver unit, a digitizing oscilloscope (or asampling board) and a computer (Not shown). Signal processing softwareis needed to extract the acoustic wave properties of the powder coreduring compaction such as travel times, reflection and transmissioncoefficients, and dispersion curves. See references by Morse et al. andKrautkramer et al. cited below. A product of the method is a computerprogram product or an article of manufacture for use in a computersystem having an operating system for use with an apparatus fordetecting, monitoring or characterizing a drug tablet during compactionthe computer program product having: a computer usable medium havingcomputer readable program code means embodied in the medium fordetecting, monitoring or characterizing a drug tablet during compaction,wherein the detecting, monitoring or characterizing includestransmitting acoustic waves into the powder core while the tablet isbeing formed; receiving acoustic waves from the powder core while thetablet is being formed; measuring data received from the receivedacoustic waves; calculating the data; and presenting the data.

Typical dwell times of the tablets in the die is on the order of a fewmilliseconds (ms) (1 ms=10-3 second). For instance, the specifiedminimum and maximum dwell times for a Presster compaction simulator(Metropolitan Computing Corporation, NJ) are listed as 5.8 ms and 230 msin the specification list for the Presster compaction simulator.

The travel time of an acoustic field in a tablet with typical dimensions(1-10 mm) is on the order of a few microseconds. Pulse repetition ratesof pulser/receiver units can be as high as a few 10s of kHz. In otherwords, a commercially available pulser receiver unit can generate highfrequency pulses with intervals as low as 0.1 ms (at a pulse repetitionrate of 10 kHz). The time-scales of these two processes (e.g. ms for thecompaction and μs for acoustic wave propagation) clearly indicate thatthe number of pulses transmitted and received in the powder core can besufficiently high (on the order of 10) and the compaction process can bemonitored via acoustic waves.

A second non-contact method described in this disclosure is to detect,monitor and characterize a drug tablet mechanical characteristics andcoating thickness.

Set-Up and Configurations

An experimental setup utilized for non-contact mechanical propertydetermination of drug tablets is illustrated in FIG. 3 and FIG. 4. FIG.3 (a) illustrates the tablet measuring portion on a non-contact system10. A pulser/receiver unit 32 excites an air-coupled transducer 14 witha square pulse. The acoustic field generated on the active surface ofthe transducer 16 interacts with the tablet 50 and the tablet'svibrational modes are excited. A laser interferometer embedded within amicroscope 44 measures the transient out-of-plane motion of a particularpoint on the surface of the vibrating tablet over a bandwidth of 20kHz-30 MHz. The interferometer includes a displacement decoder (notshown) with sub-nanometer resolution in the range of ±75 nm The diameterof the interferometric laser beam is specified as small as a fewmicrometers so that high resolution scans are possible. The setup 30, asshown in FIG. 3(b) developed for the study incorporated a squarepulser/receiver 32, an air-coupled transducer 34, a laser interferometer36, a CCD camera 38, a laser probe 40 a vibrometer controller 42 and adigitizing oscilloscope 44 (or a sampling board, not shown), as well asa vacuum handling apparatus consisting of a vacuum wand 46 and a vacuumcontrol unit 48 with a suction power of −30 kPa for holding a sampletablet 50.

Boundary conditions due to mounting techniques of a tablet have beenfound to play an important role in the accuracy and sensitivity oftransient response measurements. An ideal tablet holding configurationmust not interfere with the acoustic field exciting the vibrationalmotion of the tablet, while holding the tablet firmly with a minimalcontact area. In an exemplary embodiment, a vacuum wand is utilized forholding the tablet. The main advantages of the vacuum wand include thefirmness of grip, minimal contact surface area with the tablet, andrapidity of the handling apparatus. In experiments of the vacuum wand, aservo-motor controlled vacuum control unit is employed to automaticallycontrol suction power. As illustrated in FIGS. 4a and b , the vacuumwand is used to transport individual tablets from the tablet holdingarea to the test point.

Procedure for Determining Resonance Frequencies

Sample tablets with the average mass of 200 mg and with thecharacteristic dimensions of 5.79 mm width, 11.45 mm length, 3.33 mmthickness and a coating thickness of 102.3 μm were employed in theexperimental apparatus as shown in FIG. 5. The method equally applies totablets of different sizes. In determining the resonance frequencies ofa sample tablet, the tablet is excited by an acoustic field generated bythe air-coupled transducer 34. Since the bandwidth of the transduceroverlaps with some of the resonance frequencies of the tablet, thepropagating acoustic field generated by the air-coupled transducerexcites a number of its vibrational modes. The tablet surface transientresponses at measurement points are acquired by the interferometer in anon-contact manner by detecting the shift of a reflected laser beam andare digitized in the oscilloscope. In the vacuum wand mountingapparatus, the air-coupled transducer is placed under the sample tabletat the focal distance of the transducer (See FIG. 4). The focal distanceof the transducer used was approximately 2.35 mm. The laserinterferometer embedded into the optical microscope is directly focusedat a point on the tablet surface through the objective lens of themicroscope. The use of the microscope objective allows the laser probebeam to be focused at a spot that can be theoretically reduced to 0.5 μmusing a 100× microscope objective. The sample tablet is placed under theobjective at a distance of approximately 6.5 mm. The pulser/receiver 12unit used in this embodiment delivers a 100V square pulse to thetransmitting air-coupled transducer and provides a synchronizing pulseto trigger the digital oscilloscope (FIG. 3a ). The acquired waveformsare digitized and averaged through the digital oscilloscope 38 anduploaded to a computer 44 in order to determine the vibrationalresonance frequencies. Using an iterative computational procedurediscussed below, the mechanical properties of the sample tablet core andcoating layer can be extracted from a subset of the resonancefrequencies in a certain bandwidth.

A computer program product is used with the computer for determiningmechanical characteristics and coating thickness of a tablet thecomputer program product. The computer program product is a computerusable medium having computer readable program code means embodied inthe medium for determining the mechanical characteristics and coatingthickness and includes exciting the tablet with an acoustic field;acquiring reflected signals from the tablet; digitizing the reflectedsignals; extracting mechanical characteristics and coating thicknessfrom the resonance frequencies within a certain bandwidth and performingan iterative process to determine the mechanical characteristics andcoating thickness of the tablet.

Contact Measurements

For verification purposes, the Young's modulus of a sample tablet core(□core) is obtained using contact time-of-flight ultrasonicmeasurements. The mass densities of the core (ρ_(core)) and the coatingmaterial (ρ_(coat)) of the sample tablet are calculated from direct massmeasurements of tablets with various coating thicknesses for knowntablet geometry. Property predictions based on contact measurements areused for determining initial mechanical properties and for confirming(non-contact) experimentally obtained mechanical properties. In ofdetermining the Young's modulus of the core material (E_(core)) of thesample tablet, a direct measurement ultrasonic method (pulse-echo mode)is employed. In this test, short ultrasonic pulses are generated by apiezoelectric transducer with a central frequency to transmit throughthe tablet. The ultrasonic pulse is reflected from the back side of thetablet and returned to the measurement surface via the shortest possiblepath. The reflected waveforms are captured by the same transducer anddigitized in the oscilloscope, as illustrated in FIG. 6. The thicknessof the tablet can easily be measured precisely. The time of flight of anacoustic pulse is a function of its thickness and mass density as wellas the tablet's Young's modulus. The longitudinal velocity of soundc_(L) and Young's modulus of the core material of the tablet are easilycomputed. Consistent waveforms providing the time-of-flight across thetablet thickness for two different tablets are depicted in FIGS. 4a andb . The computed Young's modulus of the core of the sample tablet(E_(core)=2628.92 MPa) is included in Table 1. Table 1 outlines therelationships of the various properties used in the iterativecomputational procedure. p* is the vector of starting mechanicalproperty for the iterative computational procedure. p ₁ ^(e), p ₂ ^(e),p ₃ ^(e) are the extracted mechanical Property vectors upon completionof iterative procedure for p* for Tablet 1, Tablet 2, Tablet 3,respectively. p ^(c) is the measured and estimated mechanical propertyvector; E_(core) is calculated from the contact measurements, ρ_(core)and ρ_(coat) are calculated from direct mass measurements. Percentageconvergences of initial and experimental mechanical property vectors areshown for three tablets. The estimated mechanical properties (ν_(core),E_(coat), ν_(coat)) for p ^(c) are indicated by an asterisk.

TABLE 1 Convergence (%): Mechanical p*-p ₁ ^(e) Properties p* p ₁ ^(e) p₁ ^(e) p ₃ ^(e) p ^(c) Tablet 1 Tablet 2 Tablet 3 E_(core) 3154.7042648.220 2691.112 2666.287 2628.920^(†) 19.125 17.227 18.318 (MPa)P_(core) 1591.548 1335.763 1348.758 1329.848 1326.290^(†) 19.207 18.00119.679 (kg/m³) V_(core) 0.388 0.330 0.331 0.330   0.330* 17.575 17.18517.576 E_(coat) 3600.000 3023.150 3041.635 3038.521 3000* 19.081 18.35718.478 (MPa) ρ_(coat) 868.410 730.730 737.883 729.761  723.675^(†)18.841 17.689 18.999 (kg/m³) V_(coat) 0.447 0.382 0.385 0.381   0.380*17.015 16.104 17.292Finite Element Study for Tablet Spectral Properties

The spectral properties of a tablet are related to its mechanicalproperties (e.g. Young's moduli (E_(core), E_(coat)), Poisson's ratios(ν_(core), ν_(coat)) and material mass densities (ρ_(core), ρ_(coat)) ofthe core and the coating layer) as well as its geometry (e.g. shape anddimensions of the core and the coating layer). Using a finite elementalgorithm, such as the Lanczos method, the spectral properties of thetablet (e.g. a set of resonance frequencies and corresponding modeshapes) can be obtained provided that the mechanical properties andgeometry of the tablet are available. However, the extraction of thetablet mechanical properties from its measured resonance frequenciesrequires the use of an iterative computational procedure such asNewton's method as well as a method to compute its resonancefrequencies.

In the finite element study employed to compute natural frequencies ofthe tablets, a three-dimensional mesh for the tablet is modeled ashomogenous and isotropic elastic solid consisting of a core and acoating layer for numerical predictions of the tablet resonancefrequencies. The top, front and side views illustrating outer dimensionsand cross-sectional area of the coated sample tablet with a coatingthickness of 120.3 μm used in the finite element analysis are depictedin FIG. 3. Four-node linear tetrahedron elements are used in the meshgeneration for the coated tablet. The number of elements, number ofnodes, degrees of freedom and element size of the meshed coated tabletare 62,635, 14,357, 43,071, and 250 μm, respectively. The Lanczoseigenvalue solver implemented in the commercial software package ABAQUSis employed to obtain the resonance frequencies of the modeled tablet inthe frequency range of 40 kHz to 200 kHz for given material properties.

Experimental Resonance Frequency Measurements

Resonance frequencies of the tablet are obtained by applying the FastFourier Transform (FFT) algorithm on the acquired waveforms underair-coupled excitation. The frequency range of the measurements islimited to 105 kHz because 150 kHz due to the bandwidth of thetransducer employed in the experiments (See FIG. 7). In the experimentsconducted with the vacuum wand, the resonance frequencies and thedisplacement of the tablet are clearly apparent. The transient surfacedisplacement responses and frequency responses for three sample tabletswere measured utilizing the vacuum wand mounting apparatus (FIG. 8).Consistent waveforms obtained over an extended time period in theexperiments indicate that the air-coupled excitation and theexperimental set-up are repeatable and stable.

Sensitivity Analysis for Extracting Tablet Mechanical Properties

In order to extract the mechanical property parameters (E_(core),E_(coat), ν_(core), ν_(coat), ρ_(core), ρ_(coat)) of sample tablets fromtheir resonance frequencies, an iterative procedure based on Newton'smethod is adopted. From a finite element study, it is observed thatshifts in resonance frequencies are nearly linear with the reasonablechanges in the mechanical properties, and no intersection of modes isrealized within ±20% variation of the initial (estimate) mechanicalproperties. If modes traverse, the corresponding resonance frequencieswill not coincide with their ordered mode shapes and all mode shapes andrelated resonance frequencies must be verified before continuing theinversion process.

The sensitivity analysis is based on the assumption that there is awell-defined relationship between a change in certain parameters ofinterest and other parameters of interest. In this type of analysis formechanical properties, a series of either numerical or actual tests areconducted in which the (mechanical) parameters are altered toapproximate these relationships between changes in the (mechanical)parameters, and corresponding changes in the natural frequencies. Theresult of such a study is sensitivity coefficients that can be used toapproximate the assumed relationship. From these sensitivitycoefficients, the actual mechanical properties can approximately beextracted within ranges of parameters.

In the mechanical property extraction, a set of initial (estimate)mechanical property vector is chosen p _(k)* (Table 1) and thecorresponding resonance frequency vector f _(k)* is calculated via themethod (Table 2) and each iteration step is denoted by index k. Eachmechanical property parameter (E_(core), ρ_(core), ν_(core), E_(coat),ρ_(coat), ν_(coat)) and mode numbers obtained from finite element aredenoted by indices i and j, respectively. The thickness of the coat canalso be added to this vector when the coat thickness is to bedetermined. Consistent six modes calculated from finite element (j=1, 2,. . . 6) for p _(k)* compared to experimentally obtained resonancefrequencies f _(ν) ₁ ^(e), f _(ν) ₂ ^(e) f _(ν) ₃ ^(e) (Table 2) for thethree sample tablets selected for sensitivity calculations. The i-thcomponent of p _(k)* is perturbed by a factor of (1+ε) and the sixresulting perturbed material property vectors are denoted by p _(i)(i=1, 2, . . . , 6). The finite element model is run for each p _(i) todetermine the corresponding six resonance frequency vectors f _(i)* andtheir shifts Δf _(i)=f _(i)′−f*. Using the first term in Taylor'sexpansion, the sensitivity coefficient vector {s} is approximated fori=1, 2, . . . , 6 as:Δ f _(i) ≅{s} ^(T) ·{Δp}  (1)

where

$\left\{ {\Delta\; p} \right\} = \begin{Bmatrix}{\Delta\; E_{core}} & {\Delta\rho}_{core} & {\Delta\upsilon}_{core} & {\Delta\; E_{coat}} & {\Delta\rho}_{coat} & {\Delta\; v_{coat}}\end{Bmatrix}^{T}$ $\left\{ s \right\} = \begin{Bmatrix}\frac{\partial f_{j}}{\partial E_{core}} & \frac{\partial f_{j}}{\partial\rho_{core}} & \frac{\partial f_{j}}{\partial v_{core}} & \frac{\partial f_{j}}{\partial E_{coat}} & \frac{\partial f_{j}}{\partial\rho_{coat}} & \frac{\partial f_{j}}{\partial v_{coat}}\end{Bmatrix}^{T}$

j is the mode number, Δp=p _(i)−p*, {s} the sensitivity coefficientvector and Δf _(i)=f _(i)′−f*. After running the finite element modeland applying [Eq.1] for i=1, 2, . . . , 6 to calculate the sensitivitycoefficients for j=1, 2, . . . , 6, (j=7 is needed if the thickness ofthe tablet is needed) the sensitivity tangent matrix [S_(ε)]_(k) isconstructed for the selected six mode:

$\left\lbrack S_{ɛ} \right\rbrack_{k} = \begin{bmatrix}\frac{\partial f_{1}}{\partial E_{core}} & \frac{\partial f_{1}}{\partial\rho_{core}} & \frac{\partial f_{1}}{\partial v_{core}} & \frac{\partial f_{1}}{\partial E_{coat}} & \frac{\partial f_{1}}{\partial\rho_{coat}} & \frac{\partial f_{1}}{\partial v_{coat}} \\\frac{\partial f_{2}}{\partial E_{core}} & \frac{\partial f_{2}}{\partial\rho_{core}} & \frac{\partial f_{2}}{\partial v_{core}} & \frac{\partial f_{2}}{\partial E_{coat}} & \frac{\partial f_{2}}{\partial\rho_{coat}} & \frac{\partial f_{2}}{\partial v_{coat}} \\\frac{\partial f_{3}}{\partial E_{core}} & \frac{\partial f_{3}}{\partial\rho_{core}} & \frac{\partial f_{3}}{\partial v_{core}} & \frac{\partial f_{3}}{\partial E_{coat}} & \frac{\partial f_{3}}{\partial\rho_{coat}} & \frac{\partial f_{3}}{\partial v_{coat}} \\\frac{\partial f_{4}}{\partial E_{core}} & \frac{\partial f_{4}}{\partial\rho_{core}} & \frac{\partial f_{4}}{\partial v_{core}} & \frac{\partial f_{4}}{\partial E_{coat}} & \frac{\partial f_{4}}{\partial\rho_{coat}} & \frac{\partial f_{4}}{\partial v_{coat}} \\\frac{\partial f_{5}}{\partial E_{core}} & \frac{\partial f_{5}}{\partial\rho_{core}} & \frac{\partial f_{5}}{\partial v_{core}} & \frac{\partial f_{5}}{\partial E_{coat}} & \frac{\partial f_{5}}{\partial\rho_{coat}} & \frac{\partial f_{5}}{\partial v_{coat}} \\\frac{\partial f_{6}}{\partial E_{core}} & \frac{\partial f_{6}}{\partial\rho_{core}} & \frac{\partial f_{6}}{\partial v_{core}} & \frac{\partial f_{6}}{\partial E_{coat}} & \frac{\partial f_{6}}{\partial\rho_{coat}} & \frac{\partial f_{6}}{\partial v_{coat}}\end{bmatrix}$

Using [S_(ε)]_(k), the change in mechanical properties vector due to ashift {Δf _(k)} in the selected set of resonance frequencies can beapproximated by{Δ p} _(k) =[S _(ε)]_(k) ⁻¹ ·{Δf _(k)}  (2)

where Δf _(k)=f _(ν) ^(e)−f _(k)*, and {Δp}_(k) the change in mechanicalproperties after the completion of an iteration with the perturbation p_(k) ^(e)=p _(k)*+Δp _(k) (see Table 1 for their numerical values). Inthis study, a number of iterations are executed to approximate valuesfor _(core), _(coat), _(core), _(coat), _(core) and _(coat). Oncesingularity is observed in the tangent matrix [S_(ε)]_(k) or {Δp}_(k)values converge to zero the iteration loop is terminated. The values ofp* used in the last iteration correspond to the experimental mechanicalproperty vector p _(k) ^(e) of the core and coating of the tablet sinceΔp _(k)≅0 (see Table 1 for the numerical values for the three sampletablets).

A flow chart for this iterative process is depicted in FIG. 11.

After extracting the mechanical properties for each tablet, the finiteelement method is employed to determine the corresponding resonancefrequencies f ₁ ^(e), f ₂ ^(e), f ₃ ^(e) for comparison purposes (seeTable 2 for their numerical values). Due to tablet to tablet variations,small differences are detected in mechanical properties and resonancefrequencies among three sample tablets. Within ±20% variations of themechanical properties, changes in resonance frequencies are calculatedapproximately in the range of ±1.5% as listed in Table 1 and Table 2.The percent error between the experimental resonance frequencies (f _(ν)₁ ^(e), f _(ν) ₂ ^(e), f _(ν) ₃ ^(e)) and the finite element resonancefrequencies (f ₁ ^(e), f ₂ ^(e), f ₃ ^(e)) corresponding to extractedmechanical properties is within ±1.5% for three sample tablets (Table2).

TABLE 2 Convergence (%): f*-f _(i) ^(e) Modes f* f ₁ ^(e) f ₂ ^(e) f ₃^(e) Tablet 1 Tablet 2 Tablet 3 8 107,331 109,135 109,338 109,675 −1.653−1.835 −2.137 9 112,089 112,175 113,391 113,750 −0.076 −1.148 −1.460 11120,891 122,621 122,869 123,235 −1.411 −1.609 −1.902 13 122,150 123,863124,118 124,492 −1.383 −1.585 −1.881 14 131,641 131,646 133,017 133,362−0.004 −1.034 −1.290 15 136,547 138,418 138,776 138,157 −1.352 −1.606−1.165 Error (%): f ^(c)-f _(vi) ^(e) Modes f ^(c) f _(v1) ^(e) f _(v2)^(e) f _(v3) ^(e) Tablet 1 Tablet 2 Tablet 3 8 109,085 109,137 109,412109,210 −0.047 −0.298 −0.114 9 112,149 112,181 111,910 112,150 −0.0280.213 −0.00089 11 122,562 122,629 121,525 121,810 −0.054 0.853 0.617 13123,821 123,870 123,805 124,115 −0.039 0.013 −0.237 14 131,627 131,655131,220 131,830 −0.021 0.310 −0.154 15 137,425 138,480 138,505 138,155−0.762 −0.779 −0.528

f* and f ^(c) are the finite element resonance frequency vectorscorresponding to p* and p ^(c), respectively. f ₁ ^(e), f ₂ ^(e), f ₃^(e) are the finite element resonance frequency vectors, upon completionof sensitivity analysis, corresponding to p ₁ ^(e) p ₂ ^(e), p ₃ ^(e) ofTablet 1, Tablet 2, Tablet 3, respectively. f _(ν) ₁ ^(e), f _(ν) ₂^(e), f _(ν) ₃ ^(e) are the experimental resonance frequency vectorsdirectly measured with the vacuum wand for Tablet 1, Tablet 2, Tablet 3.

The sensitivity order of resonance frequencies regarding changes inmechanical properties from most to least sensitive are; E_(core),ρ_(core), E_(coat), ρ_(coat), ν_(core) and ν_(coat) (See FIG. 9).Convergence of the mechanical property parameters of Tablet 1 in theiterative loop is depicted in FIG. 8. Local convergence of eachmechanical property is also illustrated in FIG. 10.

Multi-Component Tablets

Turning to FIG. 14, a picture of a vertical cross section of a sampledry coated tablet 1400 (a special form of multi-component tablets)showing its structural components (core and coat layers) and interfacesis illustrated. The core tablet 1401 is coated on the sides (side outerlayers 1402 and 1402′), top (top outer layer 1404) and bottom (bottomouter layer 1406) layers. The core tablet 1400 has been darkened forvisualization purposes. An outer core interface 1408 and a side coreinterface 1410 are also shown. In more complex dry-coated tablets,complicated core(s) and coat layer(s) can be adopted.

FIG. 15a-c are pictures showing various other types of multi-componenttablets (as compared to FIG. 14) from consumer markets and thepharmaceutical industry. FIG. 15a shows a typical tri-layered tabletdesign; FIG. 15b shows a commercial tablet with complex layeredtablet-in-table design; FIG. 15c shows a compound tablet design withosmotic pumps and their delivery ports (orifices); and FIG. 15d showsanother multi-component tablet design that can be used as part of anembodiment of the present invention.

FIG. 16 is a schematic representation of a vibroacoustic excitation anddetection system 1600, which is used for in-die monitoring and/orcharacterizing multi-component tablets in accordance with an embodimentof the present invention. The vibroacoustic excitation and detectionsystem 1600 can include, but is not limited to, a die/punch simulator1602 which is configured/structured to contain a dry coated tablet 1400.The transmit/receive transducer 1604 can be embedded in the upper punchportion, as shown in FIG. 16, and is configured/structured to deliver anacoustic pulse 1606 directed toward the dry coated tablet 1400 for thepurpose of gathering data related to the dry coated tablet 1400 for theultimate purpose of monitoring and/or characterizing the dry coatedtablet 1400 as described herein. In other implementations of the system1600, it is contemplated that a number of transducers can be mounted inthe lower punch and/or the die in pulse-echo and/or pitch-catchconfigurations.

The transducer 1604 can be in wired or wireless communication 1608 witha vibroacoustic excitation and receiver unit 1610 (for receivingcommands from or delivering acquired data to the vibroacousticexcitation and receiver unit 1610), which can be in wired or wirelesscommunication 1608 with a digitizing oscilloscope 1612 and a computerwith specialized vibroacoustic analysis software unit 1614 (which can beconfigured/programmed to direct the other components of the system toperform the in-die monitoring and/or characterizing of multi-componenttablets in accordance with an embodiment of the present invention).Stated differently, the computer/software unit 1614 can be used forsignal processing of the acquired data from the vibroacoustic excitationand receiver unit 1610 for vibroacoustic modal analysis.

The wireless communication/transmission can be over a network (notshown), which can be any suitable wired or wireless network capable oftransmitting communication, including but not limited to a telephonenetwork, Internet, Intranet, local area network, Ethernet, onlinecommunication, offline communications, wireless communications and/orsimilar communications means. Further, the data can be encrypted ifneeded based on the sensitivity of the data or the location thedie/punch simulator 1602 or the computer/software unit 1614, forexample. Each of the components of the vibroacoustic excitation anddetection system 1600 can be located in the same room, in differentrooms in the same building, and/or in a completely different buildingand location from each other.

FIG. 17 is a schematic representation of a vibroacoustic excitation anddetection system 1700, which is used for out-of-die monitoring and/orcharacterizing multi-component tablets in accordance with an embodimentof the present invention. The vibroacoustic excitation and detectionsystem 1700 can include, but is not limited to, an upper transducer 1704connected to an upper delay line 1701, a lower transducer 1705 connectedto a lower delay line 1701′, and a dry coated tablet 1400 held betweenthe upper delay line 1701 and the lower delay line 1701′. Thevibroacoustic excitation and detection system 1700 can also include theother listed elements described with respect to and shown in FIG. 16including the vibroacoustic excitation and receiver unit 1610, which canbe in wired or wireless communication 1608 with the upper and/or lowertransducers (1704/1705), a digitizing oscilloscope 1612, and a computerwith specialized vibroacoustic analysis software unit 1614 (which can beconfigured/programmed to direct the other components of the systemperform the out-of-die monitoring and/or characterizing ofmulti-component tablets in accordance with an embodiment of the presentinvention).

Vibrational analysis (e.g. resonance (natural) frequencies, mode shapes,etc.) in addition to wave propagation analysis (e.g. Time-of-flight,dispersion properties of waves, etc.) is performed on the data collectedby each vibroacoustic excitation and detection system 1600 and 1700 withrespect to the subject multi-component tablets (materials andgeometries). In accordance with an embodiment of the present invention,the vibrational properties of a tablet (or multi-component tablet) soliddosage are taken advantage of. In brief, the resonance (natural)frequencies and mode shapes of a vibrating tablet (or multi-componenttablet) solid dosage depends on its mechanical properties and theirdistribution inside the body (such as mass density, Young's modulus,Poisson's ratio, etc.) as well as geometric characteristics (e.g. shape,dimensions, layer thicknesses, geometric irregularities etc.).Consequently, in principle, these properties and characteristics can beextracted for a tablet (or multi-component tablet) and/or theirsample-to-sample variations can be monitored when its resonance(natural) frequencies and mode shapes are experimentally available.Moreover, as material defects (e.g. degradation, faulty startingmaterials, moisture levels, etc.) and geometric irregularities (e.g.cracks, delamination, interfacial loss-of-bonding, shape and dimensionsimperfections) in a tablet (or multi-component tablet) change itsresonance (natural) frequencies and mode shapes, depending upon theextent of the defects and irregularities. Based on the experimentalmeasurements of such shifts, the quality of solid dosage can bemonitored, and defect states in tablets can be determined.

Various well-published generic computational techniques, as should beunderstood by those of skill in the art, are available to be used forthe actual numerical extractions of the resonance frequencies and modeshapes of a solid body from experimental data.

Stiction and Tooling Material Modifications on Punch and Die SurfacesDuring Compaction

Embodiments of the present invention can also include a novelnon-contact method and system for detecting and monitoring stiction andtooling material modifications (such as pitting) on the surfaces andbodies of punches and dies during compaction (which can be done in realtime) based on acoustic/ultrasonic waves. The monitoring/detecting canbe wireless, be performed in real time, and non-invasive.

FIG. 18 is a schematic representation of a system 1800 for detecting andmonitoring stiction and tooling material modifications on the surfacesand bodies of punches and dies, in accordance with an embodiment of thepresent invention. The system 1800 can include, but is not limited to, adie 1802, a lower punch 1801, and an upper punch 1803, portions of whichmay include sticking material 1807. In FIG. 18, only the stiction on theupper punch 1803 is shown, but stiction on the lower punch 1801 and die1802 can also be determined. An ultrasonic transducer 1804 is shownmounted in the upper punch. The transducer 1804, or additionaltransducers can be mounted elsewhere in the die or punches. For example,for the detection on the die side walls, transducers can be mounted inthe die material. The transducer 1804 is configured/structured todeliver an acoustic/ultrasonic waves 1806 directed toward the surfacesand bodies of punches and dies for the purpose of gathering data for theultimate purpose of detecting and monitoring stiction and toolingmaterial modifications on the surfaces and bodies of punches and dies asdescribed herein.

The transducer 1804 can be in wired or wireless communication 1808 witha ultrasonic pulser/receiver unit 1805 (for receiving commands from ordelivering acquired data to the ultrasonic pulser/receiver unit 1805),which can be in wired or wireless communication 1608 with a transmitter1809. The transmitter 1809 can be in wired or wireless communication1608 (radio waves are shown) with a receiver 1811 to transmit theacquired data to the receiver 1811. The receiver 1811 can be in wired orwireless communication with a digitizing oscilloscope 1812, which can bein wired or wireless communication 1808 with a computer with specializedvibroacoustic analysis software unit 1814 (which can beconfigured/programmed to direct the other components of the system toperform the detecting and monitoring stiction and tooling materialmodifications on the surfaces and bodies of punches and dies inaccordance with an embodiment of the present invention). The transmitter1809 and the receiver 1811 do not need to be separate devices; they canbe parts of the ultrasonic pulser/receiver 1805 and the digitizingoscilloscope respectively.

As noted elsewhere herein, the wireless communication/transmission canbe over a network (not shown), which can be any suitable wired orwireless network capable of transmitting communication, including butnot limited to a telephone network, Internet, Intranet, local areanetwork, Ethernet, online communication, offline communications,wireless communications and/or similar communications means. Further,the data can be encrypted if needed based on the sensitivity of the dataor the location the die 1802 or the computer/software unit 1814, forexample. Each of the components of the system 1800 can be located in thesame room, in different rooms in the same building, and/or in acompletely different building and location from each other.

In stiction monitoring and characterization/detection in accordance withan embodiment of the present invention, the practical interest is in themodification to the surfaces while in die/punch material modification,changes in the materials properties in the material body as well assurfaces are of interest. In the disclosed system 1800, surface and bodychanges are detected by processing the acoustic/ultrasonic waveforms(data) generated and acquired with an embedded transducer(s) 1804. Thetransducer 1804 is excited by a pulser/receiver unit 1805 as shown inFIG. 18. The state of the material body and surfaces are determined bythe analysis of such waveforms (see FIG. 20 for example).

In this disclosure, a system 1800 and a method are detailed for theobjective of real-time monitoring of the die/punch 1802/1801/1803 setsduring compaction operations. The waveforms are obtained several timesduring each cycle of the compaction operation, and are preferablytransmitted wirelessly 1808 to a local computer 1814 for analysis and/ortransmission to another user via the Internet and/or another network.See FIG. 20 for a sample waveform for a punch with no defect ormodification. The analysis software 1814 that implements the disclosedmethod produces real-time data on the state of the die/punch1802/1801/1803 sets on a compaction press. Such data and its processingcan be used for determining various operational actions, such as processcontrol (e.g. changes to the formulation and compaction pressparameters) replacement of tools, scheduling inspections, maintenanceplanning, and preventive maintenance tasks.

Any of the analyses described herein, including but not limited tovibrational analysis (e.g. resonance (natural) frequencies, mode shapes,etc.) and wave propagation analysis can be performed to determinestiction and tooling material modifications on the surfaces and bodiesof punches and dies, in accordance with an embodiment of the presentinvention.

FIG. 19 shows a photograph of an experimental set-up of system 1800 withan instrumented upper punch 1803 and tooling housing apparatus. In apreferred industrial implementation, the shown electronics can beminiaturized and integrated into punches and dies.

FIG. 20 is a graph showing tip-only waveforms from a wired (solid lines)and wireless (dotted lines) set-ups, demonstrating the differencebetween directly wired data and the noisy wireless data.

FIG. 21 shows a photograph of a compactions with material deposition(modifications) in the inner walls of a die.

Vibroacoustic Condition Monitoring of and/or Fault Diagnostics in SolidForm Compaction Presses

Embodiments of the present invention can also include a novel method andsystem for vibroacoustic condition monitoring of and/or faultdiagnostics in solid dosage compaction presses. The monitoring/faultdiagnostics can be wireless, be performed in real time, and non-invasive(aspects of which can be similar to the monitoring systems and methodsdescribed above).

As noted herein, a compaction press is an essential piece of machineryfor pharmaceutical, nutraceutical, cosmetics, metal and ceramic parts,powder and various other manufacturers for compacting powder/granularmaterial into a solid form. A typical compaction press takes powder andgranular material as raw (starting material), transfers it intocompaction dies where two punches (upper and lower) compact the materialinto a solid form under impulsive loading conditions (in a short periodof time), and collects the end product (solid forms) in a container. Theupper punch is driven into the power bed in the die with a cam driven bya motor. The lower punch is again driven by a cam and is used forejecting the solid form from the die into the presses solid formhandling system, leading the compacted products in an externalcontainer. During its operation, a compaction press generatesvibrational and acoustic signals due to a vast array of interactionsbetween its components and parts, such as punches and dies, rollers,bearings, drive shafts, and motors.

FIG. 22 is a schematic representation of a system 2200 for vibroacousticcondition monitoring of and/or fault diagnostics in solid dosagecompaction presses, in accordance with an embodiment of the presentinvention. The system 2200 can include, but is not limited to, acompaction press 2202. A close up of the compaction press 2202 is shownwith a turret 2204, a die punch set 2206, an acoustic sensor 2208 with awireless transmitter 2210 (and an antenna), and a mounted multiaxisaccelerometer 2212 with a wireless transmitter 2214 (and an antenna). Ina preferred embodiment, an array/set if multi-axis accelerometers 2212and acoustic sensors 2208 with wide spectra are employed with sensors.The mounted multiaxis accelerometer 2212 and the acoustic sensor 2208can be configured/structured to sense vibrational and acoustic signals,respectively, generated by the compaction press 2202 (which can include,for example, an array of acoustic sensors and accelerometers) and totransmit (wired, and preferably wirelessly) these signals to receivingstations—such as the acoustic sensor receiving station with antennas2211 and the accelerometer receiving station with antennas 2212.

The receiving stations 2211 and 2212 can be part of the same or separatedevice, and can be in wired or wireless communication with a computerwith a memory and specialized acoustic sensor and accelerometer analysissoftware 2214 (which can be configured/programmed to direct the othercomponents of the system to perform the monitoring of and/or faultdiagnostics in solid dosage compaction presses in accordance with anembodiment of the present invention). The computer with a memory andspecialized acoustic sensor and accelerometer analysis software 2214 canbe configured and or programmed to receive information/data from thereceiving stations 2211 and 2212 regarding parts/components of interestof a solid dosage compaction press (or a plurality of solid dosagecompaction presses), to analyze this data and determine a condition(working, not working, within specification, out of specification, etc.)and wear states of the parts/components, and to transmit (wired, andpreferably wirelessly) this information over the Internet to a decisionmaker(s) 2216.

The mounting and positioning locations of the acoustic sensors 2208multiaxis accelerometers 2212 can be determined according to the goalsof the condition monitoring and fault diagnostics that need to beperformed per a decision maker 2216. The decision maker 2216 monitoringthe state of the components and parts of the compaction press 2202onsite or off-site can determine the required actions. If the actionsare implemented by tuning the control parameters of the compaction press2202, for example, the decision maker 2216 can transmit the requiredinstructions to the compaction press central control unit 2217. If theactions involves the hardware modification (tuning, parts replacement,alignment, etc.), the decision maker can dispatche technicians,engineers, purchasing personnel, etc. to take corrective action. Thedata can also be shared with supply chain management within a company.

With the disclosed method and system, the condition and wear states ofthe components and parts of a compaction press 2202 can monitored byacquiring such vibrational and acoustic signals using the accelerometers2212 and wide-spectrum acoustic sensors 2208, wirelessly transmittingthe signals and related information to a remote control station(monitoring computer 2214) in real-time, and signal-processing thesignals by the monitoring and fault diagnostics software program 2214 todetermine condition and fault level/state of various parts andcomponents of the compaction press. The process data can be used forpreventive maintenance and remote process monitoring.

As noted elsewhere herein, the wireless communication/transmission canbe over a network (not shown), which can be any suitable wired orwireless network capable of transmitting communication, including butnot limited to a telephone network, Internet, Intranet, local areanetwork, Ethernet, online communication, offline communications,wireless communications and/or similar communications means. Further,the data can be encrypted if needed based on the sensitivity of the dataor the location the compaction press 2202 and/or the computer/softwareunit 2214, for example. Each of the components of the system 2200 can belocated in the same room, in different rooms in the same building,and/or in a completely different building and location from each other.

In this disclosure, a system 2200 and a method are detailed for theobjective of real-time monitoring of the compaction press 2202. Theaccelerometer and acoustic sensor measurements can be obtained once tomany times during each cycle of the compaction operation, and arepreferably transmitted wirelessly to the receiving stations and/ordirectly to a local computer 2014 for analysis and/or transmission toanother user via the Internet and/or another network. The analysissoftware 2014 that implements the disclosed method produces real-timedata on the state of the compaction press. Such data and its processingcan be used for determining various operational actions by the analysissoftware and/or the decision maker, such as process control (e.g.changes to the compaction press parameters) replacement of tools,scheduling inspections, maintenance planning, and preventive maintenancetasks.

Any of the analyses described herein, including but not limited tovibrational analysis (e.g. resonance (natural) frequencies, mode shapes,etc.) and wave propagation analysis can be performed to conditionmonitor the and/or perform fault diagnostics in solid dosage compactionpresses, in accordance with an embodiment of the present invention.

CONCLUSIONS AND REMARKS

In the present disclosure, a non-destructive/non-contact testingplatform for determining the mechanical properties of drug tablets hasbeen described. A computational procedure for extracting mechanicalproperty parameters from measured resonance frequencies of tablets isdeveloped and implemented. The effectiveness of the procedure forextracting the mechanical properties (Young's modulus, Poisson's ratioand mass density) of a core and coating layer of tablets from a set ofexperimentally obtained resonance frequencies is demonstrated. A mainconclusion is that mechanical properties can be extracted utilizing thediscussed experimental methodology and the iterative computationalprocedure based on subsets of the resonance frequencies of the tablet.Acquired experimental resonance frequencies agree quantitatively wellwith the finite element-based resonance frequencies corresponding to theextracted mechanical properties. Analysis also revealed that resonancefrequencies of a sample tablet are most sensitive to changes inE_(core), and least sensitive to changes in ν_(coat).

The principal applications of the methods and apparatuses disclosedinclude (i) real-time quality and mechanical integrity of tablet duringcompaction, (ii) real-time characterization of tablet propertydetermination during compaction, and (iii) specialized defect detectionand characterization methods of drug tablets.

FIG. 12 illustrates examples of potential uses of the tabletmonitoring/evaluation platform including a design of a desktop testingunit and an online monitoring system. FIG. 13 illustrates a connectivitydiagram of various components of a typical monitoring system. Thefunctions of the tablet monitoring/evaluation platform can be integratedinto an existing system.

Further, the disclosed in-die/out-of-die monitoring and/orcharacterizing of multi-component tablets approach is for determiningthe mechanical (physical), interfacial bonding and geometric (size,wall/core thicknesses, core eccentricity, and so on) quality of suchmulti-component products by acquiring and processing multi-componentproducts' responses to acoustic and vibrational excitations. Thesemechanical (physical), interfacial, and geometric properties affect themodal structure of the tablet. In this disclosed approach, thevariations in the modal response (resonance frequencies and mode shapes)are related to the mechanical (physical), interfacial, and geometricproperties using analytical/computational and statistical methods, asdisclosed herein. The disclosed method and system for in-die/out-of-diemonitoring and/or characterizing of multi-component tablets can beadopted for inline/online monitoring and characterization of such tabletproducts as well as post-production quality monitoring andcharacterization applications when the product is still in theproduction and/or in the post-production phase.

The illustrative embodiments and modifications thereto describedhereinabove are merely exemplary. It is understood that othermodifications to the illustrative embodiments will readily occur topersons of ordinary skill in the art. All such modifications andvariations are deemed to be within the scope and spirit of the presentinvention as will be defined by the accompanying claims.

What is claimed is:
 1. A method of condition monitoring of or faultdiagnostics in a solid dosage compaction press and detecting, monitoringor characterizing a drug tablet during compaction comprising the stepsof: receiving, by a processor, a first set of vibrational or acousticsignals from a portion of a compaction press; receiving, by theprocessor, a second set of vibrational or acoustic signals from a drugtablet being formed in the compaction press; analyzing, by theprocessor, data received from said first set of vibrational or acousticsignals and from the second set of vibrational or acoustic signals; anddetermining, by the processor, a first condition, a first fault state,or a first wear state of said portion of said compaction press based onsaid analyzed data received from said first set of vibrational oracoustic signals; and determining, by the processor, a quality level ofthe drug tablet or a defect state of the drug tablet based on theanalyzed data received from the second set of vibrational or acousticsignals.
 2. The method of claim 1, wherein at least one step isperformed in real time.
 3. The method of claim 2, where each of saidstep is performed in real time.
 4. The method of claim 1, furthercomprising the step of receiving, by a processor, a third set ofvibrational or acoustic signals from a portion of a compaction press. 5.The method of claim 4, further comprising the step of analyzing, by theprocessor, data received from said third set of vibrational or acousticsignals.
 6. The method of claim 5, further comprising the step ofdetermining, by the processor, a first condition, a first fault state,or a first wear state of said portion of said compaction press based onsaid analyzed data received from said third set of vibrational oracoustic signals.
 7. The method of claim 6, further comprising the stepof comparing said first determined condition, said first determinedfault state, or said first determined wear state of said portion of saidcompaction press based on said analyzed data received from said firstset of vibrational or acoustic signals with said first determinedcondition, said first determined fault state, or said first determinedwear state of said portion of said compaction press based on saidanalyzed data received from said third set of vibrational or acousticsignals.
 8. The method of claim 7, further comprising the step ofpresenting said first determined condition, said first determined faultstate, or said first determined wear state of said portion of saidcompaction press based on said analyzed data received from said thirdset of vibrational or acoustic signals on a display device.
 9. Themethod of claim 1, further comprising the step of presenting said firstdetermined condition, said first determined fault state, or said firstdetermined wear state of said portion of said compaction press based onsaid analyzed data received from said first set of vibrational oracoustic signals on a display device.
 10. The method of claim 1, furthercomprising the step of transmitting instructions to a compaction presscentral control unit to tune control parameters of the compaction pressbased on said first determined condition, said first determined faultstate, or said first determined wear state of said portion of saidcompaction press based on said analyzed data received from said firstset of vibrational or acoustic signals.
 11. A system for conditionmonitoring of or fault diagnostics in a solid dosage compaction pressand detecting, monitoring or characterizing a drug tablet duringcompaction comprising: a first acoustic sensor or accelerometerconfigured to receive a first set of vibrational or acoustic signalsfrom a portion of a compaction press and to transmit said first set ofvibrational or acoustic signals to a non-transitory computer-readablestorage medium; a second acoustic sensor configured to receive a secondset of vibrational or acoustic signals from a drug tablet being formedin the compaction press and to transmit the second set of vibrational oracoustic signals to the non-transitory computer-readable storage medium;said non-transitory computer-readable storage medium having program codefor: analyzing, by a processor, data received from said first set ofvibrational or acoustic signals, analyzing, by the processor, datareceived from the second set of vibrational or acoustic signals;determining, by the processor, a first condition, a first fault state,or a first wear state of said portion of said compaction press based onsaid analyzed data received from said first set of vibrational oracoustic signals; and determining, by the processor, a quality level ofthe drug tablet or a defect state of the drug tablet based on theanalyzed data received from the second set of vibrational or acousticsignals.
 12. The system of claim 11, wherein said non-transitorycomputer-readable storage medium further has program code for receivinga third set of vibrational or acoustic signals from a portion of acompaction press.
 13. The system of claim 12, wherein saidnon-transitory computer-readable storage medium further has program codefor analyzing data received from said third set of vibrational oracoustic signals.
 14. The system of claim 13, wherein saidnon-transitory computer-readable storage medium further has program codefor determining a first condition, a first fault state, or a first wearstate of said portion of said compaction press based on said analyzeddata received from said third set of vibrational or acoustic signals.15. The system of claim 14, wherein said non-transitorycomputer-readable storage medium further has program code for comparingsaid first determined condition, said first determined fault state, orsaid first determined wear state of said portion of said compactionpress based on said analyzed data received from said first set ofvibrational or acoustic signals with said first determined condition,said first determined fault state, or said first determined wear stateof said portion of said compaction press based on said analyzed datareceived from said third set of vibrational or acoustic signals.
 16. Thesystem of claim 14, wherein said non-transitory computer-readablestorage medium further has program code for transmitting instructions toa compaction press central control unit to tune control parameters ofthe compaction press based on said first condition, said first faultstate, or said first wear state of said portion of said compaction pressbased on said analyzed data received from said third set of vibrationalor acoustic signals.
 17. The system of claim 11, wherein saidnon-transitory computer-readable storage medium further has program codefor transmitting instructions to a compaction press central control unitto tune control parameters of the compaction press based on said firstdetermined condition, said first determined fault state, or said firstdetermined wear state of said portion of said compaction press based onsaid analyzed data received from said first set of vibrational oracoustic signals.
 18. The system of claim 11, further comprising atleast one receiving unit configured to receive said first set ofvibrational or acoustic signals from a portion of said first acousticsensor or accelerometer and to transmit said first set of vibrational oracoustic signals to said non-transitory computer-readable storagemedium.
 19. The system of claim 18, wherein said non-transitorycomputer-readable storage medium further has program code for comparingsaid calculated resonance frequency of said at least one punch or diesurface with an original resonance frequency of said at least one punchor die surface.